Mitotane With or Without Cisplatin and Etoposide After Surgery in Treating Participants With Stage I-III Adrenocortical Cancer With High Risk of Recurrence
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 40
- 试验地点
- 1
- 主要终点
- Comparison of the recurrence-free survival (RFS) status in patientis treated with adiuvant chemotherapy with or without mitotane (arm A) versus no treatment or adjuvant mitotane (arm B).
研究概览
简要总结
Adrenocortical carcinoma (ACC) is a rare endocrine malignancy. Despite complete resection of early-stage disease recurrence rates in ACC are very high (60%.70%). Patients with Ki67 ≥ 10% are considered at high risk for ACC recurrence, whereas patients with Ki67<10% are considered to have low/intermediate risk for recurrence. No study are ongoing on adjuvant systemic therapy in ACC patients that are at high risk of relapse. These patients represent 70-80% of all ACC radically operated. In this setting mitotane is widely prescribed. The efficacy of mitotane is known to be dependent on the attainment of serum drug levels in the so called therapeutic range that is above 14 mg/l. However, ACC patients with high relapse risk may develop disease recurrence before mitotane serum levels attain the target concentration. Chemotherapy with cisplatin containing regimen was shown to be efficacious in the management of ACC in few phase II trials. Based on the background, there is a strong rationale of administering chemotherapy in radically operated ACC patients with high risk of relapse defined as follows: stage I-III ACC (according to the ENSAT classification) with either microscopically complete resection (R0), microscopically positive margins (R1), or undetermined margins (RX) and Ki67≥10% (for a further definition of this condition, see the study population paragraph). In clinical practice, adjuvant mitotane alone or cisplatin-based chemotherapy or the combination of both are used worldwide in patients at high risk of relapse, but there is no prospective validation of these treatments. The investigators will test the efficacy of the combination of cisplatin plus etoposide (plus/minus mitotane according to the investigator preference) in comparison with the actual best routine practice consisting of mitotane or no therapy (according to the personal belief of clinical investigator). This study is parto of the international trial registry ADIUVO-2 coordinated by MD Anderson Center of Huston (Texas).
详细描述
Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with an annual rate of 0.5.2 cases per million population. Despite complete resection of early-stage disease recurrence rates in ACC are very high (60%.70%). Patients with Ki67 ≥ 10% are considered at high risk for ACC recurrence, whereas patients with Ki67<10% are considered to have low/intermediate risk for recurrence. Due to rarity of the disease no data from randomized clinical trials are available on the efficacy of any adjuvant therapies. Mitotane has been widely used in the adjuvant setting in ACC on the basis of the findings of a retrospective multicenter report in which relapse free survival (RFS) was significantly prolonged in patients treated with adjuvant mitotane compared with two control groups who were not given mitotane. The retrospective design of this study resulted in controversy about the benefit of adjuvant mitotane and led to a prospective clinical trial to compare mitotane to placebo as adjuvant therapy in low-risk/intermediate-risk ACC patients who have low Ki67 expression (<10%; ADIUVO study, ClinicalTrials.gov Identifier: NCT00777244).
No study are ongoing on adjuvant systemic therapy in ACC patients that are at high risk of relapse. These patients represent 70-80% of all ACC radically operated. In this setting mitotane is widely prescribed. The efficacy of mitotane is known to be dependent on the attainment of serum drug levels in the so called therapeutic range that is above 14 mg/l. These mitotane levels should be maintained over time. The results of a recent retrospective analysis on the impact of serum mitotane levels on prognosis in 122 ACC patients, who were radically resected, showed that the 63 patients who reached and maintained the target mitotane concentrations during follow-up had a significantly lower rate of recurrence than the 59 patients who failed to keep mitotane levels as high. However, the attainment of therapeutic range of mitotane usually require 2-3 months whatever is the schedule adopted. ACC patients with high relapse risk may develop disease recurrence before mitotane serum levels attain the target concentration.
Chemotherapy with cisplatin containing regimen was shown to be efficacious in the management of ACC in few phase II trials.
The results of the only phase III trial conducted up to now, the FIRM-ACT study, found that mitotane combined with cisplatin-based chemotherapy was superior to mitotane combined with streptozocin in terms of progression free survival and overall survival in patients with advanced/metastatic ACC. The cytotoxic activity of chemotherapy is rapid and this is the rationale of administering a cisplatin containing regimen in adjuvant setting of ACC patients with high risk of disease relapse.
Adjuvant mitotane treatment improved RFS and overall survival (OS) in a retrospective study, and adjuvant mitotane is undergoing prospective evaluation in low-risk/intermediate-risk ACC patients (Ki67<10%; ADIUVO study). However, Mitotane alone could be not adequate as adjuvant therapy in highly proliferating ACC since the drug efficacy is strictly dependent on the attainment of circulating concentration levels >14 mg/l that is usually achieved after 2-3 months of therapy. In this lead time disease recurrence may occur.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Histologically confirmed diagnosis of ACC (Weiss score of ≥ 3); all tumor specimens can be reviewed a posteriori by a reference pathologis
- •High risk of relapse within 60 days of surgical resection of primary tumor with curative intent with either microscopically complete resection (R0, microscopically positive margins (R1), or undetermined margins (RX, based on surgical or pathological reports without unequivocal evidence of metastasis in the perioperative imaging).
- •Ki67≥10% (to be determined by an experienced pathologist in each participating center and preferably via quantitative imaging analysis).
- •Have perioperative imaging (CT with contrast or MRI of the chest/abdomen/pelvis) demonstrating no unequivocal evidence of disease within 4 weeks before randomization. Patients with indeterminate non-specific nodules (<1 cm for soft tissue lesions and <1.5 cm in the short dimension for lymph nodes) will be permitted to participate in this study.
- •Be 18 years old or older.
- •Have a negative pregnancy test no more than 7 days before starting treatment
- •Adequate contraception
- •Have an Eastern Cooperative Oncology Group performance status 0.2
- •Have an adequate bone marrow reserve (neutrophils >1,000/mm3 and/or platelets >80,000/mm3)
- •Have an adequate organ function (including renal, liver and cardiac function)
- •Be able to comply with the protocol procedures and provide written informed consent.
排除标准
- •The time between primary surgery and randomization is >60 days
- •They have undergone repeated surgery for recurrence of disease
- •They have a history of recent or active prior malignancy, except for cured non-melanoma skin cancer, cured in situ cervical carcinoma, breast ductal carcinoma in situ, or other treated malignancies where there has been no evidence of disease for at least 2 years
- •They have renal insufficiency (estimated glomerular filtration rate [GFR] <50 mL/min/1.73 m2) or significant liver insufficiency (serum bilirubin>2 times the upper normal range and/or serum alanine aminotransferase [ALT] or aspartate aminotransferase [AST]>3 times the upper normal range). GFRs will be calculated according to the validated formula (MDRD)
- •They are pregnant or breast feeding
- •They have congestive heart failure (ejection fraction<45%). In patients with a history of cardiac disease, a baseline two-dimensional echocardiogram is needed to document ejection fraction. In patients without prior cardiac disease, a baseline electrocardiogram (EKG) is sufficient if there is no evidence of acute ischemic changes or prior evidence of myocardial infarction. If EKG results are abnormal (ischemic changes, significant arrhythmia, or suggestion of prior myocardial infarction), a two-dimensional echocardiogram will be obtained to assess ejection fraction
- •They have preexisting grade 2 peripheral neuropathy
- •They underwent previous or current treatment with mitotane or other antineoplastic drugs for ACC
- •They underwent previous radiotherapy for ACC
- •They have any other severe acute or chronic medical or psychiatric condition or laboratory abnormality that would impart, in the judgment of the investigator, excess risk associated with study participation or study drug administration or that, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
研究组 & 干预措施
A - adjuvant therapy
adjuvant therapy with four cycles of cisplatin plus etoposide +/- mitotane according to investigator's preference versus
干预措施: Cisplatin plus Etoposide (Drug)
A - adjuvant therapy
adjuvant therapy with four cycles of cisplatin plus etoposide +/- mitotane according to investigator's preference versus
干预措施: Observation or Mitotane (Other)
B - observation or mitotane alone
observation or mitotane alone according to the investigator's preference
干预措施: Observation or Mitotane (Other)
结局指标
主要结局
Comparison of the recurrence-free survival (RFS) status in patientis treated with adiuvant chemotherapy with or without mitotane (arm A) versus no treatment or adjuvant mitotane (arm B).
时间窗: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 36 months
Evaluation of recurrence-free survival (RFS). Recurrence will be objectively assessed every 16 weeks by imaging the chest/abdomen/pelvis by either computed tomography (CT; with slice thickness of 5 mm or less) or magnetic resonance imaging (MRI). Suspected lesions will be accurately measured in at least one dimension (the longest diameter in the plane of measurement will be recorded). Soft tissue lesions must have a minimum size of 10 mm, and suspected malignant lymph nodes must be more than 15 mm (short axis) to be considered pathological.
次要结局
- Assessment of toxicity and adverse events(From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 36 months)
- Assessment of the predictive role of Ki67 expression for chemotherapy efficacy(Ki67 expression evaluated at the screening phase)
- Assessment of the predictive role of histopathologic characteristics (Weiss-score) for chemotherapy efficacy(Weiss score identified at the screening phase)
- Assessment of overal survival(From date of randomization until the date of death from any cause, assessed up to 36 months)
研究者
Alfredo Berruti
Head of Oncology Unit
Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia